Artemether attenuates renal tubular injury by regulating iron metabolism in mice with streptozotocin-induced diabetes.

OBJECTIVES: Renal tubular injury plays an important role in the progression of diabetic kidney disease. Previous studies demonstrated that artemether, an antimalarial agent, exerts renal tubular protection in diabetes. However, the detailed mechanisms remain unclear. Several studies have indicated that disorders of iron metabolism have a great impact on renal tubular injury. Therefore, this study was performed to explore whether the therapeutic effects of artemether on diabetic renal tubular injury are related to iron metabolism. METHODS: Male C57BL/6 J mice were randomly divided into three groups. Mice in the type 1 diabetic (T1D) control and streptozotocin (STZ) groups were fed a regular diet; mice in the STZ plus artemether (STZ+Art) group were treated with artemether. RESULTS: Artemether significantly reduced the urinary albumin:creatinine ratio and tubular injury in mice with T1D. Artemether also restored the energy imbalance and restored the changes of mitochondrial cristae in mice with T1D. Increased protein and mRNA levels of ferritin heavy chain (FTH) and ferritin light chain (FTL) were observed in renal tubules of diabetic mice. In response to iron overload, levels of iron transport-related proteins and the antioxidant system related to iron metabolism were abnormal in diabetic mice. Artemether significantly restored the protein and mRNA expression levels of both FTH and FTL. Both the iron transport and antioxidant systems were also restored by artemether to varying degrees. CONCLUSIONS: Artemether attenuates renal tubular injury in diabetic mice; this effect might be related to its regulation of iron metabolism.

Artemether Alleviates Diabetic Kidney Disease by Modulating Amino Acid Metabolism.

Diabetes is a worldwide metabolic disease with rapid growing incidence, characterized by hyperglycemia. Diabetic kidney disease (DKD), the leading cause of chronic kidney disease (CKD), has a high morbidity according to the constantly increasing diabetic patients and always develops irreversible deterioration of renal function. Though different in pathogenesis, clinical manifestations, and therapies, both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) can evolve into DKD. Since amino acids are both biomarkers and causal agents, rarely report has been made about its metabolism which lies in T1DM- and T2DM-related kidney disease. This study was designed to investigate artemether in adjusting renal amino acid metabolism in T1DM and T2DM mice. Artemether was applied as treatment in streptozotocin (STZ) induced T1DM mice and db/db T2DM mice, respectively. Artemether-treated mice showed lower FBG and HbA1c and reduced urinary albumin excretion, as well as urinary NAG. Both types of diabetic mice showed enlarged kidneys, as confirmed by increased kidney weight and the ratio of kidney weight to body weight. Artemether normalized kidney size and thus attenuated renal hypertrophy. Kidney tissue UPLC-MS analysis showed that branched-chain amino acids (BCAAs) and citrulline were upregulated in diabetic mice without treatment and downregulated after being treated with artemether. Expressions of glutamine, glutamic acid, aspartic acid, ornithine, glycine, histidine, phenylalanine and threonine were decreased in both types of diabetic mice whereas they increased after artemether treatment. The study demonstrates the initial evidence that artemether exerted renal protection in DKD by modulating amino acid metabolism.

Combination therapy with artemether and enalapril improves type 1 diabetic nephropathy through enhancing antioxidant defense.

Previous studies have demonstrated that both artemether and enalapril are effective in treating diabetic nephropathy (DN). However, the effects and underlying mechanisms of their combination in treating DN remain unknown. The experimental DN model was induced by injecting streptozotocin (STZ) into male C57BL/6J mice. Mice were randomly allocated to the Type 1 diabetes control (T1D-ctrl), STZ, STZ + artemether (STZ + Art), STZ + enalapril (STZ + ACEi), or STZ + artemether + enalapril (STZ + Art + ACEi) group. The interventions lasted for 8 weeks. At the end of the experiment, related urine and serum biochemical values, such as urinary albumin excretion (UAE) and fasting blood glucose (FBG), were measured. In addition, blood pressure (BP) and kidney morphologic changes were also evaluated. The expression of oxidative stress related molecules, such as catalase, acetylated SOD2 (k68) and acetylated SOD2 (k122) in the kidney were measured. Results: combination therapy showed more pronounced effects in reducing UAE, FBG, and BP than any single drug. Typical diabetic kidney injuries, such as heavier kidney weight, and glomerular and tubular hypertrophy, were also further alleviated by combination therapy. Combination therapy also up-regulated the expression of catalase and down-regulated the expression of acetylated SOD2 (k68) and acetylated SOD2 (k122). Combination therapy with artemether and enalapril exhibited renoprotective effects in STZ-induced T1D mice superior to a single drug. The mechanism might be associated with their synergistic effects in enhancing antioxidant defense.

Gut Dysbiosis with Minimal Enteritis Induced by High Temperature and Humidity.

High temperature and humidity (HTH) can cause diarrhea owing to food and drinking water contamination. However, their direct effects on gut microbiota and gastrointestinal inflammation are unknown. This study aimed to investigate the effects of HTH and probiotics on the microbiome. Twenty-one male mice were randomly assigned to normal control (NC), HTH, and broad-spectrum probiotic-treated (PR) groups. HTH and PR groups were regularly housed at 30 ± 0.5 °C with humidity of 85-90% for eight consecutive weeks. A broad-spectrum probiotic was administrated to PR-group mice from day 50 to 56. Clinical signs were observed and gut microbiota were analyzed via 16 S rRNA-based functional metagenomics. Intestinal pathology and the expression of defensins and pro-inflammatory cytokines were also assessed. Mice in the HTH and PR groups gradually developed sticky or loose feces. The HTH group developed a distinct microbiota profile associated with augmented metabolism and human-like pathophysiologies upon suppression of environmental sensing. Pathological assays indicated minimal enteritis, increased bacterial translocation, and elevated intestinal pro-inflammatory cytokine levels. Thus, ambient HTH directly contributes to gut dysbiosis and minimal enteritis, whereas probiotics partially normalized the microbiota and ameliorated gut inflammation. This study provides novel insights into the pathogenesis of environment-associated diseases and offers a potential therapeutic approach.

Three Constituents of Moringa oleifera Seeds Regulate Expression of Th17-Relevant Cytokines and Ameliorate TPA-Induced Psoriasis-Like Skin Lesions in Mice.

As a folk medicine, Moringa oleifera L. is used effectively to treat inflammatory conditions and skin diseases. However, its mechanism of action is not well understood, limiting its medical use. We isolated and identified three compounds, namely niazirin, marumoside A and sitosterol-3-O-ß-d-glucoside, from the seeds of Moringa oleifera, and studied their effects on the expression of Th17-relevant cytokines (IL-12/IL-23 p40, IL-17A, IL-22 and IL-23 p19) using lipopolysaccharide-stimulated THP-1 cells. Additionally, as Th17 plays a critical role in the pathogenesis of psoriasis, we used a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced psoriasis-like skin lesion mouse model to study their potential therapeutic application in vivo. The compounds suppressed the expression of IL-12/IL-23 p40, IL-17A, IL-22 and IL-23 p19 in vitro, and in vivo they ameliorated psoriasis-like skin lesions, decreased IL-17A mRNA expression, and increased the expression of keratinocyte differentiation markers. To our knowledge, this is the first report regarding the mechanism and therapeutic application of Moringa oleifera seeds to treat psoriasis-like lesions in vivo.